Metformin attenuates angiotensin II-induced TGFβ1 expression by targeting hepatocyte nuclear factor-4-α
| Autor: | Han Xiao, Dan Li, Jianshu Zhang, Qiang Shen, Youyi Zhang, Ruifei Chen, Yao Song, Jimin Wu, Yenan Feng, Zhizhen Lu, Hao Li |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Pharmacology medicine.medical_specialty Activator (genetics) business.industry Cardiac fibrosis AMPK medicine.disease Angiotensin II Metformin 03 medical and health sciences Hepatocyte nuclear factors 030104 developmental biology Endocrinology Hepatocyte nuclear factor 4 Fibrosis Internal medicine cardiovascular system medicine business medicine.drug |
| Zdroj: | British Journal of Pharmacology. 175:1217-1229 |
| ISSN: | 0007-1188 |
| DOI: | 10.1111/bph.13753 |
| Popis: | Background and Purpose Metformin, a small molecule antihyperglycaemic agent, is well-known as an AMP-activated protein kinase (AMPK) activator and protects against cardiac fibrosis. However, the underlying mechanisms remain elusive. Transforming growth factor-β1 (TGFβ1) is a key cytokine mediating cardiac fibrosis. Here, we investigated the effects of metformin on TGFβ1 production induced by angiotensin II (AngII) and the underlying mechanisms. Experimental Approach Wild-type and AMPKα2-/- C57BL/6 mice were subcutaneously injected with metformin or saline and infused with AngII (3 mg kg-1 day-1) for 7 days. Adult mouse cardiac fibroblasts (CFs) were isolated for in vitro experiments. Key Results In CFs, metformin inhibited AngII-induced TGFβ1 expression via AMPK activation. Bioinformatics analysis predicted a potential hepatocyte nuclear factor 4α (HNF4α)-binding site in the promoter region of the Tgfb1 gene. Overexpressing HNF4α increased TGFβ1 expression in CFs. HNF4α siRNA attenuated AngII-induced TGFβ1 production and cardiac fibrosis in vitro and in vivo. Metformin inhibited the AngII-induced increases in HNF4α protein expression and binding to the Tgfb1 promoter in CFs. In vivo, metformin blocked the AngII-induced increase in cardiac HNF4α protein levels in wild-type mice but not AMPKα2-/- mice. As the consequence, metformin inhibited AngII-induced TGFβ1 production and cardiac fibrosis in wild-type mice but not AMPKα2-/- mice. Conclusions and Implications HNF4α mediated AngII-induced TGFβ1 transcription and cardiac fibrosis. Metformin inhibited AngII-induced HNF4α expression via AMPK activation, thus decreasing TGFβ1 transcription and cardiac fibrosis. These findings reveal a novel antifibrotic mechanism of action of metformin and identify HNF4α as a new potential therapeutic target for cardiac fibrosis. |
| Databáze: | OpenAIRE |
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